Cadmium Studies Suggest New Pathway to Human Cancer

Researchers at the National Institute of Environmental Health Sciences(http://www.niehs.nih.gov) today reported that cadmium - a naturally occurring metal which shows up in food, water and cigarette smoke - disturbs a DNA repair system that is important in preventing cancer.

"Unless cadmium is unique in its mechanism," NIEHS' Dmitry A. Gordenin, Ph.D., said, "it would seem that environmental factors may cause genetic defects and cancer not only by attacking our DNA directly but also by undermining the mechanisms by which faulty DNA replication is repaired." Dr. Gordenin is the senior author of the paper which he and his colleagues reported in today's issue of the journal Nature Genetics(http://www.nature.com/ng/).

A naturally present white metal, cadmium already is listed in the federal Report on Carcinogens(http://ntp.niehs.nih.gov/NewHomeRoc/AboutRoC.html) as a "known human carcinogen" and has long been known to cause human lung cancer in cadmium-related industry if safeguards are not taken. The new studies, in yeast and human cells, are intended to show how this happens.

Soon after the discovery of the DNA double helix 50 years ago, studies showed environmental chemicals and stresses could cause mutations that could result in uncontrolled cell growth, leading to cancer. But the NIEHS group's new contribution is to show that cadmium causes mutations in another way - by inhibiting the ability of cells to repair routine errors made when the DNA is copied to make new cells.

Without the repairs, cells mutate "dramatically" and multiply.

The initial studies were done in yeast cells - the living cells used to make bread rise - which have proved a useful tool for studying cellular activities. Previous work has demonstrated that what happens in yeast cells generally also happens in more complex life forms, like humans. And the researchers said that studies with extracts of human cells and initial studies in cultured human cells also suggest a similar mechanism.

Dr. Gordenin said, "Cells must duplicate their DNA in order to increase their numbers enough to replace dying cells. However, in duplicating the DNA mistakes are made with a frequency that organisms would not be able to tolerate, if uncorrected. Luckily, most organisms do correct these mistakes by efficient mechanisms akin to a computer's "spell-check." One of these correctives is post-replication mismatch repair. Without these corrective mechanisms, mutations would occur and multiply in cell after cell, which could lead to cancer, reproductive problems, birth defects or other ills.

"What we have shown," Dr. Gordenin continued, "is that environmental factors such as cadmium can cause high levels of mutations not only by damaging DNA directly but also by inhibiting DNA repair."

Michael A. Resnick, Ph.D., an NIEHS senior scientist and a co-author of the report, said, "What cadmium exposure does in living cells is to block post-replication mismatch repair of natural errors and thus increase the mutations dramatically - as much as 2,000 fold. Genetically, this can result in a vast increase in errors that could be catastrophic."

Thomas A. Kunkel, Ph.D., another NIEHS senior scientist on the project, said that the amount of cadmium needed to inhibit repair and increase mutations was remarkably small. "We saw substantial effect from cadmium exposure from concentrations that may well be environmentally relevant especially to cadmium-related industry workers and smokers."

Cadmium is a natural element in the earth, found in all soils and rocks, including coal and fertilizers. It is used in metal coatings, plastics and batteries, partly because it does not corrode easily. Although workers in these industries may be exposed to greater concentrations, the general population can be exposed to cadmium from breathing cigarette smoke, drinking contaminated water or eating foods that contain it. Smoking doubles the average daily intake.

Until 1997, cadmium carbonate and cadmium chloride were used as fungicides for golf courses and home lawns.

Cadmium disappears from organisms very slowly. Its half-life in the human body can be as long as 20 years.

Yong Hwan Jin, Ph.D., is the first author on the study report today. Other co-authors are Alan B. Clark, Robbert (sic) J.C. Slebos, Ph.D., Hanan Al-Refai and Jack A Taylor, Ph.D. Dr. Taylor is with both the NIEHS Laboratory of Molecular Carcinogenesis and the Epidemiology Branch. Dr. Slebos is with the Laboratory of Molecular Carcinogenesis. The other scientists are with the Laboratory of Molecular Genetics.

The National Institute of Environmental Health Sciences is an institute of the federal National Institutes of Health(http://www.nih.gov) within the Department of Health and Human Services(http://www.hhs.gov) . NIEHS' laboratories are in Research Triangle Park, a science enclave between Raleigh, Durham and Chapel Hill, N.C. The National Toxicology Program, which produces the federal government's Report on Carcinogens - the list of known and reasonably anticipated human carcinogens referred to in paragraph two - is headquartered at the NIEHS.

The research is appearing today in the on-line version of Nature Genetics and will be published soon in the paper version of the journal.

NIEHS supports research to understand the effects of the environment on human health and is part of NIH. For more information on environmental health topics, visit http://www.niehs.nih.gov (http://www.niehs.nih.gov/index.cfm) . Subscribe to one or more of the NIEHS news lists ( http://www.niehs.nih.gov/news/newslist/index.cfm (http://www.niehs.nih.gov/news/newsroom/newslist/index.cfm) ) to stay current on NIEHS news, press releases, grant opportunities, training, events, and publications.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov (http://www.nih.gov/).